Lung cancer remains the leading cause of cancer related mortality in both men and women and is estimated to cause 28% of all cancer deaths in 2008. Molecular analysis of lung carcinomas has identified a small number of genetic lesions such as activation of oncogenes and inactivation of tumor suppressor genes that appear to be critical for their development and maintenance. Recently, somatic mutations of the LKB1 tumor suppressor gene have been added to this list. In a mouse model of lung adenocarcinoma, LKB1 deletion on a backdrop of mutant Kras activation results in a shorter tumor latency, an expanded histological spectrum, and a propensity towards metastasis. We have observed that the hypoxia-inducible factor (HIF) family member, HIF2, is upregulated upon LKB1 loss and that in LKB1-deficient lung cancer cell lines knock- down of HIF2 results in the induction of markers of apoptosis, suggesting that HIF2 mediates the survival of LKB1-deficient lung cancers. We hypothesize that HIF2 is a critical downstream mediator of LKB1 loss and propose: 1) To determine whether HIF2 activation correlates with LKB1 mutation in a large dataset of human lung tumors. 2) To determine whether the phenotype induced by LKB1 loss is dependent upon HIF2 in vitro. 3) To determine whether the phenotypes induced by LKB1 loss are dependent upon HIF2 in vivo.